DSB REPAIR RECOMBINATION, AND GENOME STABILITY

DSB 修复重组和基因组稳定性

• 批准号: 7198028
• 负责人: Jac A Nickoloff
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-18 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198028
• 关键词: Biochemical; Cells; Chemicals; Chromatin Structure; Complement; Complementary DNA; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA biosynthesis; DNA lesion; DNA repair protein; DNA-PKcs; Data; Defect; Dimerization; Dominant-Negative Mutation; Double Strand Break Repair; Frequencies; G22P1 gene; Genetic; Genetic Recombination; Genome Stability; Genomic Instability; Goals; Intervention; Lead; Link; Loss of Heterozygosity; Malignant Neoplasms; Mediating; Molecular Conformation; NBS1 gene; Nature; Outcome; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Predisposition; Proteins; Radiation; Radiation therapy; Regulation; Relative (related person); Research; Role; Syndrome; Testing; Thinking; XRCC5 gene; cancer therapy; improved; insertion/deletion mutation; insight; leukemia/lymphoma; link protein; neoplastic cell; recombinational repair; repaired

DESCRIPTION (provided by applicant): The goal of the proposed research is to determine how proteins at the interface of homologous recombinational repair (HR) and nonhomologous end-joining (NHEJ) modulate DNA double-strand break (DSB) repair fidelity. Defects in HR and NHEJ proteins are linked to cancer predisposition. DSBs are key DNA lesions produced by genotoxic chemicals and radiation, and DSBs may arise spontaneously during DNA replication. HR and NHEJ compete for the repair of DSBs, and the genetic consequences of the two repair pathways are significantly different. Many factors are likely to influence the choice between HR and NHEJ, some of which are substrate-dependent. Perhaps more important from the standpoint of potential targets for chemo- or radiotherapeutic intervention in cancer treatment are trans factors, i.e., DNA repair proteins, including their concentrations, physical interactions, and biochemical activities. HR and NHEJ may compete passively for DSBs, with each operating independently of the other. Alternatively, competition may be active, with HR proteins interacting with, and modulating the activities of NHEJ proteins, and vice versa. Although most DSB repair proteins have been assigned to the HR or the NHEJ pathway, some influence both pathways, such as the MRE11/RAD50/NBS1 (MRN) complex. Recent evidence indicates that DNAPKcs and Ku are also at the NHEJ/HR interface. These proteins therefore play important roles in determining the genetic consequences of DSB damage. Other data indicate that DNA-PKcs, Ku, and MRN also regulate spontaneous HR, suggesting another mechanism by which these proteins regulate genome stability. Our central hypothesis is that proteins at the HR/NHEJ interface regulate genome stability by controlling the relative levels and outcomes of NHEJ and HR during DSB repair, and by controlling spontaneous FIR levels. We will determine how DSB repair is regulated by DNA-PKcs (Aim 1), Ku (Aim 2), MRN (Aim 3), and we will determine if spontaneous HR is regulated by these proteins (Aim 4). These projects will provide insight into the regulation of mammalian DSB repair and spontaneous HR that can be exploited to develop more effective agents to sensitize tumor cells to DNA damaging agents, and thereby improve cancer therapy.

描述（由申请人提供）：拟议的研究的目的是确定同源重组维修（HR）界面处的蛋白质如何调节DNA双链（DSB）修复保真度。 HR和NHEJ蛋白的缺陷与癌症易感性有关。 DSB是由遗传毒性化学物质和辐射产生的关键DNA病变，在DNA复制过程中可能会自发出现DSB。 HR和NHEJ竞争DSB的维修，两种修复途径的遗传后果显着差异。许多因素可能会影响HR和NHEJ之间的选择，其中一些因素依赖于底物。从癌症治疗中化学或放射治疗的潜在靶标的角度来看，也许更重要的是反式因素，即DNA修复蛋白，包括其浓度，物理相互作用和生化活性。人力资源和NHEJ可能会被动地与DSB进行被动竞争，每个人都独立于另一个。另外，竞争可能是活跃的，HR蛋白与NHEJ蛋白的活性相互作用并调节竞争，反之亦然。尽管大多数DSB修复蛋白已分配给HR或NHEJ途径，但有些影响两种途径，例如MRE11/RAD50/NBS1（MRN）复合物。最近的证据表明，DNAPKC和KU也处于NHEJ/HR界面。因此，这些蛋白质在确定DSB损伤的遗传后果方面起着重要作用。其他数据表明，DNA-PKC，KU和MRN还调节自发的人力资源，这表明了这些蛋白质调节基因组稳定性的另一种机制。我们的中心假设是，HR/NHEJ界面处的蛋白质通过控制DSB修复期间NHEJ和HR的相对水平和结果以及控制自发的FIR水平，从而调节基因组稳定性。我们将确定DSB修复如何受DNA-PKC（AIM 1），KU（AIM 2），MRN（AIM 3）调节，我们将确定是否由这些蛋白质调节自发HR（AIM 4）。这些项目将提供有关调节哺乳动物DSB修复和自发人力资源的洞察力，这些修复和自发HR可以开发以开发更有效的剂，以使肿瘤细胞对DNA损害剂敏感，从而改善癌症治疗。